Drug-resistant bacteria, particularly methicillin-resistant Staphylococcus aureus (MRSA) infection, is violently spreading in the seven main global medical market areas. In America, community-acquired MRSA infection is on the rise. According to recent research data, 9% of patients with infectious diseases in UK National Health Service (NHS) hospitals acquired the infection through surgical operations or outpatient services; about 100,000 people suffer from the invasion of the infection every year, and about 5,000 people die, and moreover, it can cause the expenditure of more than 1 billion pounds. Thus the seriousness of the MRSA infection is evident.
Tigecycline is the first glycylcycline antibiotic approved for clinical intravenous administration, similar to tetracyclines in structure, and was developed by Wyeth and is on the market. Glycylcycline antibiotic preparations are derivatives of minocycline. The mechanism of action of tetracyclines is that tetracyclines bind to the A site of the 30S ribosome to prevent amino acid charged transfer RNA from entering the ribosome, thereby blocking the formation of peptide chains with amino acid residues. Glycylcyclines are similar to the tetracyclines in their mechanism of action, but have higher affinity than the latter. Glycylcyclines directly interact with another area of the A site of the ribosome. Tigecycline inhibits the formation of the peptide chains and influences the structural formation of bacteria and the realization of certain functions so as to kill the bacteria or inhibit bacterial reproduction.
Research shows that tigecycline can be used for adult intra-abdominal infections (cIAI) and complicated skin and soft tissue infections (cSSSI) caused by Escherichia coli, Enterococcus faecalis (only vancomycin-susceptible strains), Staphylococcus aureus (methicillin-susceptible and resistant strains), Streptococcus agalactiae, Streptococcus anginosus genus (including Streptococcus anginosus, Streptococcus anginosus intermedius, and Streptococcus constellatus), Streptococcus pyogenes and Bacteroides fragilis, Citrobacter freundii, Aerobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumonia, Enterococcus faecalis (only vancomycin-susceptible strains), Staphylococcus aureus (only methicillin-susceptible strains), Bacteroides thetaiotaomicron, Bacteroides uniformis, Clostridium perfringens, Peptostreptococcus micros and the like. Tigecycline has the characteristic that the antibacterial spectrum is broad.
In addition, research also shows that tigecycline can overcome two main drug-resistance mechanisms, efflux pump and ribosome protection, which have limited the use of many antibiotics. Therefore, tigecycline does not develop drug-resistance easily, and will be applicable in a very broad range.
Tigecycline is not stable enough in solution, and is easily subjected to breakage due to oxidation degradation and epimerization, and the breakage can be accelerated by heating; a common solution is that tigecycline is prepared into a freeze-dried powder for injection; however, we found that even if tigecycline is prepared into a freeze-dried preparation, the stability of tigecycline during preparation, transportation and storage cannot be guaranteed, related substances in the preparation are still significantly increased, moreover, the requirements for the formulation and infusion time in clinical use are stringent, and thus this will be very inconvenient and hidden danger will be brought to the safety of patients taking the medication.
CN 101132775 A discloses a freeze-dried powder for injection consisting of tigecycline and a suitable carbohydrate. The occurrence of oxidation and epimerization in the powder for injection is also effectively inhibited by the formulation. The suitable carbohydrate disclosed by Wyeth is lactose, and was validated by the FDA and approved to appear on the market. However, according to the lactose standards in the 2010 version of China Pharmacopeia, lactose can only be used as an excipient of an oral preparation. Lactose is not used as the injection excipient in any National Formulary in the world at present, potential safety hazards may be brought about by using lactose as the excipient for injection, and moreover, the proportion of lactose intolerance of Asian people is higher, and adverse effects caused by lactose intolerance may be increased.
In order to broaden the applicable range of people and lower the clinical use risk, and increase the stability of tigecycline at the same time, the invention provides a novel tigecycline composition for injection.